The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics.

UNLABELLED: Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as 'GB multiforme'). GB is the most common and aggressive primary malignant brain tumor and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but is upregulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype; (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue; and (iii) TWEAK: Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells.

Age-related changes in motor control during articulator visuomotor tracking.

The present study provides normative data on changes in visuomotor control of the oral-facial system across the lifespan. Control of the lower lip, jaw, and larynx (i.e., fundamental frequency) was examined using a nonspeech visuomotor tracking (VMT) task, where subjects move the articulator of interest to track a moving target on an oscilloscope screen. This task examines articulator motor control during movements that are similar to speech but that do not impose linguistic units or the demands of coordinating multiple structures. Accuracy and within- and between-subject variability in tracking performance were measured by cross correlation, gain ratio, phase shift, and target-tracker amplitude difference. Cross-correlation analyses indicated that performance of children (aged 8;2 to 17;0 [years;months]) and older adults (aged 45;1 to 84;3) is poorer than that of younger adults (aged 17;1 to 45;0). Accuracy of movement amplitude tended to increase during development and decline with aging, whereas age did not appear to influence accuracy of temporal parameters in lip and jaw tracking. In contrast, age tended to influence individual variability in temporal but not amplitude parameters. Differences were noted between articulators. The data complement previous studies that considered accuracy and variability of articulator movement during speech. The VMT method and the data provided may be applied to assessment of impairments in the motor speech system and to differential diagnosis of motor speech versus linguistically based disorders.

Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator.

BACKGROUND: Sedating antihistamines may impair driving performance as seriously as alcohol. OBJECTIVE: To compare the effects of fexofenadine, diphenhydramine, alcohol, and placebo on driving performance. DESIGN: Randomized, double-blind, double-dummy, four-treatment, four-period crossover trial. SETTING: The Iowa Driving Simulator. PARTICIPANTS: 40 licensed drivers with seasonal allergic rhinitis who were 25 to 44 years of age. INTERVENTION: One dose of fexofenadine (60 mg), diphenhydramine (50 mg), alcohol (approximately 0.1% blood alcohol concentration), or placebo, given at weekly intervals before participants drove for 1 hour in the Iowa Driving Simulator. MEASUREMENTS: The primary end point was coherence, a continuous measure of participants' ability to match the varying speed of a vehicle that they were following. Secondary end points were drowsiness and other driving measures, including lane keeping and response to a vehicle that unexpectedly blocked the lane ahead. RESULTS: Participants had significantly better coherence after taking alcohol or fexofenadine than after taking diphenhydramine. Lane keeping (steering instability and crossing the center line) was impaired after alcohol and diphenhydramine use compared with fexofenadine use. Mean response time to the blocking vehicle was slowest after alcohol use (2.21 seconds) compared with fexofenadine use (1.95 seconds). Self-reported drowsiness did not predict lack of coherence and was weakly associated with minimum following distance, steering instability, and leftlane excursion. CONCLUSIONS: Participants had similar performance when treated with fexofenadine or placebo. After alcohol use, participants performed the primary task well but not the secondary tasks; as a result, overall driving performance was poorer. After participants took diphenhydramine, driving performance was poorest, indicating that diphenhydramine had a greater impact on driving than alcohol did. Drowsiness ratings were not a good predictor of impairment, suggesting that drivers cannot use drowsiness to indicate when they should not drive.

Driving simulation study: bilateral array multifocal versus bilateral AMO monofocal intraocular lenses.

PURPOSE: To determine whether differences exist in the driving performance of patients with bilateral Array multifocal intraocular lenses (IOLs) and those with bilateral AMO monofocal IOLs under low-contrast environmental conditions. SETTING: The Iowa Driving Simulator at the Center for Computer Aided Design, the University of Iowa, Iowa City, Iowa, USA. METHODS: This prospective study was a test-operator-masked, parallel-group comparison of the driving performance of 33 bilateral multifocal IOL patients and 33 bilateral monofocal IOL patients from the U.S. Array Multifocal study. Driving performance was evaluated under 3 poor visibility conditions (clear weather at night, clear weather at night in the presence of a glare source, and fog). Measures of performance included recognition rates and distances for signs, as well as detection rates, distances, and avoidance behaviors for hazards. Contrast acuity and sensitivity were also measured to evaluate possible correlations with driving performance. RESULTS: No statistically significant differences between the IOL groups were found in 26 of 30 comparisons (86.7%). The monofocal group performed better than the multifocal group in comparisons in which there were statistically significant differences: the percentage of correctly recognized warning signs at night in clear weather (P = .028), sign recognition distances for guide (P = .030) and warning (P = .036) signs in fog, and the detection distance for 1 of 4 hazards (suitcase; P = .026). Correlation coefficients between driving performance and low-contrast acuity and sensitivity were statistically significant; however, they were low and not likely predictive of driving performance. CONCLUSION: Differences between patients with bilateral multifocal IOLs and those with bilateral monofocal IOLs were detected; however, the results indicate no consistent difference in driving performance and safety.

Surgical management of Bell's palsy.

OBJECTIVES: Incomplete return of facial motor function and synkinesis continue to be long-term sequelae in some patients with Bell's palsy. The aim of this report is to describe a prospective study in which a well-defined surgical decompression of the facial nerve was performed in a population of patients with Bell's palsy who exhibit the electrophysiologic features associated with poor outcomes. In addition, management issues related to Bell's palsy including herpes simplex virus typel etiology, the natural history, electrodiagnostic testing, and efficacy of surgical strategies are reviewed. STUDY DESIGN AND METHODS: A multicenter prospective clinical trial was designed utilizing electroneurography (ENOG) and voluntary electromyography (EMG) to identify patients with Bell's palsy who would most likely develop poor return of facial function, as suggested by Fisch and Esslen. Patients who displayed electrodiagnostic features of poor outcome, >90% degeneration on ENOG testing and no voluntary motor unit EMG potentials within 14 days of onset of total paralysis, were offered a surgical decompression of the facial nerve through a middle cranial fossa surgical exposure, including the tympanic segment, geniculate ganglion, labyrinthine segment, and meatal foramen. Control subjects were those who displayed similar electrodiagnostic features and time course. RESULTS: Subjects who did not reach 90% degeneration on ENOG within 14 days of paralysis all returned to House-Brackmann grade I (n = 48) or II (n = 6) at 7 months after onset of the paralysis. Control subjects self-selecting not to undergo surgical decompression when >90% degeneration on ENOG and no motor unit potentials on EMG were identified had a 58% chance of developing a poor outcome at 7 months after onset of paralysis (House-Brackmann grade III or IV [n = 19]). A group with similar ENOG and EMG findings undergoing middle fossa facial nerve decompression exhibited House-Brackmann grade I (n = 14) or II (n = 17) in 91% of the cases. An exact permutation test confirmed that the surgical group had a significantly higher proportion of patients with a good outcome (House-Brackmann grade I or II) (P = .0002). CONCLUSION: Electroneurography in combination with voluntary EMG successfully identified patients who will most likely return to normal from those who had a greater chance of long-term sequelae from Bell's palsy. Surgical decompression medial to the geniculate ganglion significantly improves the chances of normal or near-normal return of facial function in the group that has a high probability of a poor result. Surgical decompression must be performed within 2 weeks of onset of total paralysis for it to be effective.

Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness.

CONTEXT: Mutations in the GJB2 gene are the most common known cause of inherited congenital severe-to-profound deafness. The carrier frequency of these mutations is not known. OBJECTIVES: To determine the carrier rate of deafness-causing mutations in GJB2 in the midwestern United States and the prevalence of these mutations in persons with congenital sensorineural hearing loss ranging in severity from moderate to profound, and to derive revised data for counseling purposes. DESIGN: Laboratory analysis, performed in 1998, of samples from probands with hearing loss for mutations in GJB2 using an allele-specific polymerase chain reaction assay, single-strand conformation polymorphism analysis, and direct sequencing. SETTING AND SUBJECTS: Fifty-two subjects younger than 19 years sequentially referred to a midwestern tertiary referral center for hearing loss or cochlear implantation, with moderate-to-profound congenital hearing loss of unknown cause, parental nonconsanguinity, and nonsyndromic deafness with hearing loss limited to a single generation; 560 control neonates were screened for the 35delG mutation. MAIN OUTCOME MEASURE: Prevalence of mutations in the GJB2 gene by congenital deafness status. RESULTS: Of 52 sequential probands referred for congenital sensorineural hearing loss, 22 (42%) were found to have GJB2 mutations. The 35delG mutation was identified in 29 of the 41 mutant alleles. Of probands' sibs, all homozygotes and compound heterozygotes had deafness. Fourteen of 560 controls were 35delG heterozygotes, for a carrier rate expressed as a mean (SE) of 2.5% (0.66%). The carrier rate for all recessive deafness-causing GJB2 mutations was determined to be 3.01% (probable range, 2.54%-3.56%). Calculated sensitivity and specificity for a screening test based on 35delG mutation alone were 96.9% and 97.4%, respectively, and observed values were 94% and 97%, respectively. CONCLUSIONS: Our data suggest that mutations in GJB2 are the leading cause of moderate-to-profound congenital inherited deafness in the midwestern United States. Screening of the GJB2 mutation can be offered to individuals with congenital deafness with high sensitivity and specificity by screening only for the 35delG mutation. A positive finding should establish an etiologic diagnosis and affect genetic counseling.

Psychological change over 54 months of cochlear implant use.

OBJECTIVE: To determine the long-term psychological outcome of postlingually deafened adults who received multichannel cochlear implants and to relate the psychological outcome to audiological outcome. DESIGN: Thirty-seven recipients of multichannel cochlear implants who participated in a prospective clinical trial completed psychological assessments before implantation and at regularly scheduled follow-ups through 54 mo of implant use. Standardized measures of affect, social function, and personality were used, and scores on these measures were correlated with asymptotic scores on several audiological measures. RESULTS: Evidence of significant improvement on measures of loneliness, social anxiety, and distress were obtained within a year after implantation and throughout the duration of the follow-up period. For measures of assertiveness and marital satisfaction, improvement was apparent only after long-term implant use. Although favorable changes on the Minnesota Multiphasic Personality Inventory (MMPI) Depression Scale were evidenced only in the initial follow-up period, improvements on the MMPI Paranoia and Social Introversion Scales persisted throughout the 54 mo follow-up. CONCLUSION: Multichannel cochlear implant use is associated with long-term psychological benefit. Correlations between audiological outcome and psychological outcome, however, suggested that the relation between audiological benefit and psychological benefit is not simple.

Electrically evoked compound action potentials of guinea pig and cat: responses to monopolar, monophasic stimulation.

We recorded electrically evoked compound action potentials (EAPs) from guinea pigs and cats using monophasic current pulses delivered by a monopolar intracochlear electrode. By using simple stimuli, we sought results that could shed light on basic excitation properties of the auditory nerve. In these acute experiments, the recording electrode was placed directly on the auditory nerve. Responses to anodic and cathodic stimulus pulses were recorded separately to evaluate stimulus polarity effects. Several polarity-dependent properties were observed. Both EAP morphology and latency were polarity-dependent, with greater latencies for cathodic stimulation. Threshold stimulus level was also polarity-dependent, but in different directions in the two species: cats had lower cathodic thresholds while guinea pigs had lower anodic thresholds. We also observed that the slopes of the EAP amplitude-level functions depended upon stimulus polarity. In most cases where EAP saturation amplitude could be measured, that amplitude was similar for anodic and cathodic stimuli, suggesting that either stimulus polarity can recruit all fibers, or at least a comparable numbers of fibers. The common findings (e.g., EAP morphology and polarity-dependent latency) observed in these two species suggest results that can be extrapolated to responses obtained in humans, while the species-specific findings (e.g., dependence of threshold on polarity) may point to underlying anatomical differences that caution against overgeneralization across species. Some of our observations also bear upon hypotheses of how electrical stimuli may excite different sites on auditory nerve fibers.

Timbral recognition and appraisal by adult cochlear implant users and normal-hearing adults.

The purpose of this study was to examine the appraisal and recognition of timbre (four different musical instruments) by recipients of Clarion cochlear implants (CIS strategy, 75- or 150-microsec pulse widths) and to compare their performance with that of normal-hearing listeners. Twenty-eight Clarion cochlear implant users and 41 normal-hearing listeners were asked to give a subjective assessment of the pleasantness of each instrument using a visual analog scale with anchors of "like very much" to "dislike very much," and to match each sound with a picture of the instrument they believed had produced it. No significant differences were found between the two different pulse widths for either appreciation or recognition; thus, data from the two pulse widths following 12 months of Clarion implant use were collapsed for further analyses. Significant differences in appraisal were found between normal-hearing listeners and implant recipients for two of the four instruments sampled. Normal-hearing adults were able to recognize all of the instruments with significantly greater accuracy than implant recipients. Performance on timbre perception tasks was correlated with speech perception and cognitive tasks.

5'-Peptidyl substituents allow a tuning of the affinity of oligodeoxyribonucleotides for RNA.

The affinity of amide-linked 5'-aminoacyl and 5'-dipeptidyl DNA octamers for two RNA undecamers with 3'-overhangs was measured via UV melting analysis. A sequence-dependent increase in melting points was observed. At low ionic strength, two appended lysine residues elevate melting points more than two additional A:U base pairs.

Performance of 2- and 3-year-old children and prediction of 4-year from 1-year performance.

OBJECTIVE: To examine whether children perform better when they receive cochlear implants when they are 2 to 4 years of age than when they are older, and to determine whether 4-year performance can be predicted from 1-year results. METHOD: Children in two age groups (2 to 4, 4 to 9 years) were tested for performance, and the age groups were compared. Children were also tested 1 and 4 years after implantation. RESULTS: The results suggest that the "implanted young" group scored higher than the "implanted old" group after 36 months, and that 1-year performance is helpful in predicting 4-year performance. CONCLUSION: It may be desirable for children to undergo implantation when they are under 2 years of age, provided that appropriate selection criteria can be determined.

Speech perception by prelingually deaf children using cochlear implants.

In this investigation we measured the performance of 50 prelingually deaf children on several speech perception tests. Children were from 2 to 15 years of age, and some children were tested with as much as 5 years of cochlear implant use. Speech perception tests included the recognition of stress pattern, consonants, vowels, words, and sentences. The audiovisual perception of consonants was also measured. Average results indicated that gains were being made in the perception of stress and words in a closed-set context within 1 year from implantation. The perception of words in an open-set context demonstrated much slower increases over time. Large individual differences were observed. Some preliminary data suggest that children who receive implants before the age of 4 years obtain higher scores, on average, than children who receive implants after the age of 5 years. Some children become part-time users or nonusers of their cochlear implants. The average results from 18 congenitally deaf children were significantly higher than the average results from 12 children with prelingually acquired deafness after 3 years of implant use. Information on vowel and consonant features shows increases in performance after 2 years of cochlear implant use, with the exception of the place feature. For this feature, no changes were observed. Vision-alone testing indicated that lipreading performance increased over time. An audiovisual enhancement provided by the cochlear implant was observed for all features.

Performance over time of adult patients using the Ineraid or nucleus cochlear implant.

This study examined the average and individual performance over time of 49 adult cochlear implant subjects. Subjects were randomly assigned to receive either the Ineraid cochlear implant, with analog processing, or the Nucleus cochlear implant, with feature-extraction processing. All subjects had postlingual profound bilateral sensorineural hearing loss and received no significant benefit from hearing aids before implantation. Group data were examined in two ways. First, only subjects who had complete data over the test period were examined. Second, an analysis of all available data was carried out by mixed linear-model analysis. In this analysis, to account for missed follow-ups at the planned intervals, data consisting of the observations closest in time to the planned test times were modeled by natural splines with knots at the planned follow-up times. Contrasts between all pairs of planned follow-up times for each device were tested, as were contrasts between devices at each planned follow-up time. Results indicated little difference between the performance of the Ineraid and Nucleus subjects in their level of performance or their rate of learning. Postimplantation performance was typically superior to preimplantation performance within 9 months, and continued to improve up to 18-30 months depending on the speech perception measure. In some subjects, improvements in speech perception measures were observed up to four or five years postimplantation. There was also evidence that three subjects had a decrement in overall speech perception performance, although their postimplantation scores were always higher than their preimplantation scores. In at least one subjects this was likely a result of age-related cognition decrements.

Perception of rhythmic and sequential pitch patterns by normally hearing adults and adult cochlear implant users.

OBJECTIVE: This study compares the musical perception of 17 adult recipients of the Nucleus cochlear implant using two different formant extraction processing strategies (F0F1F2 and MPEAK). DESIGN: Over a 12 mo period, participants were alternately switched between two strategies every 3 mo. Performance was evaluated using three measures of rhythmic and sequential pitch perception. RESULTS: Three individuals performed significantly better with the MPEAK strategy on one particular rhythm task, 11 participants performed better with the MPEAK strategy on another rhythm task, and no significant differences were found between the two strategies on a sequential pitch pattern task. CONCLUSIONS: Neither strategy seems clearly superior for perception of either sequential pitch or rhythmic patterns.

Cochlear implant use by prelingually deafened children: the influences of age at implant and length of device use.

This study focused on long-term speech perception performances of 34 prelingually deafened children who received multichannel cochlear implants manufactured by Cochlear Corporation. The children were grouped by the age at which they received cochlear implants and were characterized by the amount of time they used their device per day. A variety of speech perception tests were administered to the children at annual intervals following the connection of the external implant hardware. No significant differences in performance are evident for children implanted before age 5 compared to children implanted after age 5 on closed-set tests of speech perception ability. All children demonstrated an improvement in performance compared to the pre-operative condition. Open-set word recognition performance is significantly better for children implanted before age 5 compared to children implanted after age 5 at the 36-month test interval and the 48-month test interval. User status, defined by the amount of daily use of the implant, significantly affects all measures of speech perception performance except pattern perception.

Initial independent results with the Clarion cochlear implant.

OBJECTIVE: This paper reports some preliminary findings from patients, implanted at the University of Iowa, using the Advanced Bionics Clarion cochlear implant (version 1.0). We compared the performance of patients using both simultaneous analog and nonsimultaneous pulsatile processing strategies. The performance of Clarion patients was also compared with a group of patients who were using either the feature-extraction Nucleus cochlear implant or the compressed-analog Ineraid cochlear implant. DESIGN: One aim was to compare the analog and pulsatile stimulation in 19 patients using the Clarion implant. This aim could be accomplished only partially because of difficulties encountered in adequately fitting patients with the analog strategy. A second aim was to compare the Clarion users' performance with feature-extraction Nucleus and compressed-analog Ineraid patients. Comparisons were made with all patients having 9 mo experience postimplantation. RESULTS: Subjects performed better using the pulsatile mode compared with the analog mode. All subjects chose to use the pulsatile strategy after the first 3 mo of the study. Results comparing performance at 9 mo with our compressed-analog Ineraid and feature-extraction Nucleus patients indicated, in general, better average performance for the Clarion users. CONCLUSIONS: We conclude that the pulsatile version of the Clarion cochlear implant typically produces superior performance to the analog version of that device at this stage in its development. After 9 mo of experience, users of the Clarion implant are performing better than are users of the feature-extraction Nucleus and compressed-analog Ineraid cochlear implants with comparable amounts of experience.